Glycerol Inhibits Water Permeation through Plasmodium Falciparum Aquaglyceroporin

TL;DR

This study demonstrates that glycerol binds within PfAQP, blocking water permeation by occupying the pore, which has significant implications for understanding the protein's function and regulation in malaria parasites.

Contribution

It reveals glycerol's inhibitory role in water transport through PfAQP by identifying a bound state inside the pore, a novel insight into aquaglyceroporin regulation.

Findings

Glycerol binds with a dissociation constant of ~14 μM inside PfAQP.

Bound glycerol occludes the pore, inhibiting water and permeant transport.

The structure facilitates van der Waals interactions critical for glycerol binding.

Abstract

Plasmodium falciparum aquaglyceroporin (PfAQP) is a multifunctional membrane protein in the plasma membrane of P. falciparum, the parasite that causes the most severe form of malaria. The current literature has established the science of PfAQP's structure, functions, and hydrogen-bonding interactions but left unanswered the following fundamental question: Does glycerol modulate water permeation through aquaglyceroporin that conducts both glycerol and water? This paper provides an affirmative answer to this question of essential importance to the protein's functions. On the basis of the chemical-potential profile of glycerol from the extracellular bulk region, throughout PfAQP's conducting channel, to the cytoplasmic bulk region, this study shows the existence of a bound state of glycerol inside aquaglyceroporin's permeation pore, from which the dissociation constant is approximately 14 microM. A glycerol molecule occupying the bound state occludes the conducting pore through which permeating molecules line up in single file by hydrogen-bonding with one another and with the luminal residues of aquaglyceroporin. In this way, glycerol inhibits permeation of water and other permeants through aquaglyceroporin. The biological implications of this theory are discussed and shown to agree with the existent in vitro data. It turns out that the structure of aquaglyceroporin is perfect for the van der Waals interactions between the protein and glycerol to cause the existence of the bound state deep inside the conducting pore and, thus, to play an unexpected but significant role in aquaglyceroporin's functions.